Recent studies demonstrate that an increased blood concentration of a soluble form of the Mannose Receptor (MR) correlates with the severity of various inflammatory diseases. Therefore, the soluble MR (sMR)has been postulated as a biomarker for macrophage activation.
In this project, we directly investigate the influence of the sMR on macrophage functionality in the context of metaflammation. We demonstrated that blood sMR levels correlate with the bodyweight of HFD-treated mice and with the BMI of obese humans. Mechanistically, the sMR directly binds to CD45 on macrophages, inhibiting its phosphatase activity and resulting in the activation of Src kinase, Akt and NFkB, finally leading to macrophage reprogramming towards an inflammatory phenotype. Concomitantly, MR-deficient HFD-treated mice showed a significant reduction in inflammatory macrophages and fat accumulation and protection against liver steatosis. Importantly, direct injection with sMR resulted in increased concentrations of TNF, IL6 and IL1b in the serum, increase of inflammatory macrophages in fat tissue, impairments in whole body metabolism and weight gain, substantiating an important role of the MR in metaflammation
In this proposal, we investigate the mechanisms underlying MR shedding and the effect of the sMR on lipid metabolism in adipocytes. Furthermore, we analyze sMR concentrations on a population level and investigate whether sMR concentrations correlate with other inflammatory diseases. Finally, we search for molecules inhibiting sMR-mediated macrophage activation.